Delta d-crystalline form of ivabradine hydrochloride, a process for its preparation and pharmaceutical compositions containing it

ABSTRACT

A δd-crystalline form of ivabradine hydrochloride of formula (I):  
                 
characterised by its powder X-ray diffraction data. Medicinal products containing the same which are useful as bradycardics.

The present invention relates to the δd-crystalline form of ivabradine hydrochloride of formula (I)

to a process for its preparation and to pharmaceutical compositions containing it.

Ivabradine, and addition salts thereof with a pharmaceutically acceptable acid, and more especially its hydrochloride, have very valuable pharmacological and therapeutic properties, especially bradycardic properties, making those compounds useful in the treatment or prevention of various clinical situations of myocardial ischaemia such as angina pectoris, myocardial infarct and associated rhythm disturbances, and also in various pathologies involving rhythm disturbances, especially supraventricular rhythm disturbances, and in heart failure.

The preparation and therapeutic use of ivabradine and addition salts thereof with a pharmaceutically acceptable acid, and more especially its hydrochloride, have been described in the European patent specification EP 0 534 859.

In view of the pharmaceutical value of this compound, it has been of prime importance to obtain it with excellent purity. It has also been important to be able to synthesise it by means of a process that can readily be converted to the industrial scale, especially in a form that allows rapid filtration and drying. Finally, that form had to be perfectly reproducible, easily formulated and sufficiently stable to allow its storage for long periods without particular requirements for temperature, light or oxygen level.

The patent specification EP 0 534 859 describes a synthesis process for ivabradine and its hydrochloride. However, that document does not specify the conditions for obtaining ivabradine in a form that exhibits those characteristics in a reproducible manner.

The Applicant has now found that a particular salt of ivabradine, the hydrochloride, can be obtained in a well defined crystalline form that exhibits valuable characteristics for stability and processability.

More specifically, the present invention relates to the δd-crystalline form of ivabradine hydrochloride, characterised by the following powder X-ray diffraction diagram, measured using a PANalytical X'Pert Pro diffractometer together with an X'Celerator detector and expressed in terms of line position (Bragg's angle 2 theta, expressed in degrees), line height (expressed in counts), line area (expressed in counts x degrees), line width at half-height (“FWHM”, expressed in degrees) and interplanar distance d (expressed in Å): Area Line Angle 2 theta Height (counts × FWHM Interplanar no. (degrees) (counts) degrees) (degrees) distance (Å) 1 4.1 414 41 0.1004 21.672 2 6.8 176 139 0.8029 13.078 3 8.6 1020 101 0.1004 10.305 4 9.1 323 43 0.1338 9.687 5 10.9 224 30 0.1338 8.100 6 11.7 354 47 0.1338 7.592 7 14.6 2774 458 0.1673 6.074 8 15.3 1805 328 0.184 5.800 9 16.6 986 163 0.1673 5.345 10 17.2 3821 946 0.2509 5.153 11 18.1 2290 378 0.1673 4.898 12 19.1 440 73 0.1673 4.649 13 19.6 289 38 0.1338 4.526 14 20.1 650 86 0.1338 4.408 15 20.9 887 146 0.1673 4.252 16 21.4 3112 565 0.184 4.147 17 22.1 1708 254 0.1506 4.027 18 22.5 1191 275 0.2342 3.945 19 23.4 619 102 0.1673 3.800 20 23.9 1343 222 0.1673 3.728 21 24.7 256 34 0.1338 3.604 22 25.6 309 41 0.1338 3.482 23 26.2 1899 313 0.1673 3.397 24 26.9 1588 183 0.1171 3.310 25 27.6 1357 224 0.1673 3.231 26 29.1 140 37 0.2676 3.069 27 29.5 145 29 0.2007 3.023

The invention relates also to a process for the preparation of the δd-crystalline form of ivabradine hydrochloride, which process is characterised in that acetonitrile or a mixture of acetonitrile and water is preheated, ivabradine hydrochloride is added, the solution obtained is allowed to cool at room temperature, held at room temperature until crystallisation is complete, and the crystals formed are dehydrated.

-   -   In the crystallisation process according to the invention it is         possible to use ivabradine hydrochloride obtained by any         process, for example ivabradine hydrochloride obtained by the         preparation process described in patent specification EP 0 534         859.     -   The solution may advantageously be seeded during the cooling         step.     -   The acetonitrile or mixture of acetonitrile and water is         preferably preheated to a temperature between 60° C. and reflux,         more preferably between 65 and 75° C.     -   The dilution is preferably more than 15 ml/g, more preferably         between 50 and 100 ml/g.     -   The dehydration is preferably performed by heating.

The invention relates also to pharmaceutical compositions comprising as active ingredient the δd-crystalline form of ivabradine hydrochloride together with one or more appropriate, inert and non-toxic excipients. Among the pharmaceutical compositions according to the invention there may be mentioned, more especially, those that are suitable for oral, parenteral (intravenous or subcutaneous) or nasal administration, tablets or dragées, sublingual tablets, capsules, lozenges, suppositories, creams, ointrnents, dermal gels, injectable preparations and drinkable suspensions.

The useful dosage can be varied according to the nature and severity of the disorder, the administration route and the age and weight of the patient. The dosage varies from 1 to 500 mg per day in one or more administrations.

The Examples that follow illustrate the invention.

The X-ray powder diffraction spectrum was measured under the following experimental conditions:

-   -   PANalytical X'Pert Pro diffractometer, X'Celerator detector,         temperature-regulated chamber,     -   voltage 45 kV, intensity 40 mA,     -   mounting θ-θ,     -   nickel (Kβ) filter,     -   incident-beam and diffracted-beam Soller slit : 0.04 rad,     -   automatic divergence slits: irradiated length of 10 mm,     -   mask: 10 mm,     -   antiscatter slit: 1/2°,     -   measurement mode: continuous from 3° to 30°, in increments of         0.017°,     -   measurement time per step : 19.7 s,     -   total time : 4 min 32 s,     -   measurement speed : 0.108°/s.

EXAMPLE 1 δd-crystalline Form of Ivabradine Hydrochloride

160 ml of acetonitrile are preheated to 70° C. and then 2 g of ivabradine hydrochloride obtained according to the process described in patent specification EP 0 534 859 are added, in portions, with stirring until dissolution is complete. The solution is then stored at ambient temperature for 2 days. The crystals are removed by filtration in vacuo and are spread out onto a crystallisation plate. The crystals are then heated to a temperature of 85° C. at a rate of 10° C./min and held at 85° C. for 4 hours.

Powder X-ray Diffraction Diagram:

The powder X-ray diffraction profile (driffraction angles) of the δd-form of ivabradine hydrochloride is given by the significant lines collated in the following table: Area Line Angle 2 theta Height (counts × FWHM Interplanar no. (degrees) (counts) degrees) (degrees) distance (Å) 1 4.1 414 41 0.1004 21.672 2 6.8 176 139 0.8029 13.078 3 8.6 1020 101 0.1004 10.305 4 9.1 323 43 0.1338 9.687 5 10.9 224 30 0.1338 8.100 6 11.7 354 47 0.1338 7.592 7 14.6 2774 458 0.1673 6.074 8 15.3 1805 328 0.184 5.800 9 16.6 986 163 0.1673 5.345 10 17.2 3821 946 0.2509 5.153 11 18.1 2290 378 0.1673 4.898 12 19.1 440 73 0.1673 4.649 13 19.6 289 38 0.1338 4.526 14 20.1 650 86 0.1338 4.408 15 20.9 887 146 0.1673 4.252 16 21.4 3112 565 0.184 4.147 17 22.1 1708 254 0.1506 4.027 18 22.5 1191 275 0.2342 3.945 19 23.4 619 102 0.1673 3.800 20 23.9 1343 222 0.1673 3.728 21 24.7 256 34 0.1338 3.604 22 25.6 309 41 0.1338 3.482 23 26.2 1899 313 0.1673 3.397 24 26.9 1588 183 0.1171 3.310 25 27.6 1357 224 0.1673 3.231 26 29.1 140 37 0.2676 3.069 27 29.5 145 29 0.2007 3.023

EXAMPLE 2 Pharmaceutical Composition

Formula for the preparation of 1000 tablets each contaning 5 mg of ivabradine base: Compound of Example 1 5.39 g Maize starch 20 g Anhydrous colloidal silica 0.2 g Mannitol 63.91 g PVP 10 g Magnesium stearate 0.5 g 

1. A δd-crystalline form of ivabradine hydrochloride of formula (I):

exhibiting essentially the following powder X-ray diffraction data, measured using a PANalytical X'Pert Pro diffractometer together with an X'Celerator detector and expressed in terms of line position (Bragg's angle 2 theta, expressed in degrees), line height (expressed in counts), line area (expressed in counts x degrees), line width at half-height (“FWHM”, expressed in degrees) and interplanar distance d (expressed in Å): Area Line Angle 2 theta Height (counts × FWHM Interplanar no. (degrees) (counts) degrees) (degrees) distance (Å) 1 4.1 414 41 0.1004 21.672 2 6.8 176 139 0.8029 13.078 3 8.6 1020 101 0.1004 10.305 4 9.1 323 43 0.1338 9.687 5 10.9 224 30 0.1338 8.100 6 11.7 354 47 0.1338 7.592 7 14.6 2774 458 0.1673 6.074 8 15.3 1805 328 0.184 5.800 9 16.6 986 163 0.1673 5.345 10 17.2 3821 946 0.2509 5.153 11 18.1 2290 378 0.1673 4.898 12 19.1 440 73 0.1673 4.649 13 19.6 289 38 0.1338 4.526 14 20.1 650 86 0.1338 4.408 15 20.9 887 146 0.1673 4.252 16 21.4 3112 565 0.184 4.147 17 22.1 1708 254 0.1506 4.027 18 22.5 1191 275 0.2342 3.945 19 23.4 619 102 0.1673 3.800 20 23.9 1343 222 0.1673 3.728 21 24.7 256 34 0.1338 3.604 22 25.6 309 41 0.1338 3.482 23 26.2 1899 313 0.1673 3.397 24 26.9 1588 183 0.1171 3.310 25 27.6 1357 224 0.1673 3.231 26 29.1 140 37 0.2676 3.069 27 29.5 145 29 0.2007 3.023


2. A process for the preparation of the δd-crystalline form of ivabradine hydrochloride of claim 1, wherein acetonitrile or a mixture of acetonitrile and water is preheated, ivabradine hydrochloride is added, the solution obtained is allowed to cool at room temperature, held at room temperature until crystallization is complete, and the crystals formed are dehydrated.
 3. The process of claim 2, wherein the solution of ivabradine hydrochloride is seeded during the cooling step.
 4. A pharmaceutical composition comprising as active ingredient the δd-crystalline form of ivabradine hydrochloride of claim 1, in combination with one or more pharmaceutically acceptable, inert, non-toxic carriers.
 5. A method for treating or preventing a condition requiring a bradycardic, such method comprising the step of administering to a living animal body, including a human, a therapeutically effective amount of δd-crystalline form of ivabradine hydrochloride of claim
 1. 6. A method for treating or preventing clinical situations of myocardial ischaemia and/or a condition involving rhythm disturbances, such method comprising the step of administering to a living animal body, including a human, a therapeutically effective amount of δd-crystalline form of ivabradine hydrochloride of claim
 1. 7. The method of claim 6, wherein the clinical situations of myocardial ischaemia is selected form angina pectoris, myocardial infarct and associated rhythm disturbances.
 8. The method of claim 6, wherein the condition involving rhythm disturbances is selected from supraventricular rhythm disturbances and heart failure. 